The main objective of the proposal is to develop site-specific and site-activated ophthalmic drugs, based on the recently discovered reductive process-activated chemical delivery system. In the analogy of the established 1) reduction, 2) hydrolytic sequence production of epinephrine specifically in the iris-ciliary body, it is proposed to develop new site-activated drugs in the iris-ciliary body from ketone-type precursors of 1) sympathomimetic amines and 2) Beta-adrenergic blocking agents. The proposed approach aims at development of new types of ophthalmic drugs with significantly reduced local and systemic toxicity, thus much improved therapeutic index. The proposed studies will also provide important information about the enzymatic processes in the various parts of the eye, particularly the relative rates of reductive and hydrolytic processes. The scope and limitations (structural requirements) of the ketone reductase activity in the iris-ciliary body will be established. Correlation between partition coefficients and membrane transport properties of ophthalmic drugs will also be established. The proposed studies include 1) synthesis of a variety of ketone-ester type chemical delivery systems for sympathomimetic amines like isoproterenol, terbutaline and phenylephrine. 2) For Beta-adrenergic blocking agents like propranolol and timolol. 3) In vivo enzymatic conversion studies of the combined ketone-ester type chemical delivery systems and of the proposed oxime precursors. 4) In vivo metabolism-activation studies of selected compounds. 5) In vivo activity studies (mydriasis and IOP reduction, respectively). The ultimate objective is to develop novel types of antiglaucoma drugs of low toxicity and high specificity, as well of new ophthalmic diagnostic agents.